title: Neuropeptide orphanin FQ inhibits dendritic morphogenesis through activation of RhoA.
abstract: Brain-derived neurotrophic factor (BDNF) plays a facilitatory role in neuronal development and promotion of differentiation. Mechanisms that oppose BDNF's stimulatory effects create balance and regulate dendritic growth. However, these mechanisms have not been studied. We have focused our studies on the BDNF-induced neuropeptide OrphaninFQ/ Nociceptin (OFQ); while BDNF is known to enhance synaptic activity, OFQ has opposite effects on activity, learning, and memory. We have now examined whether OFQ provides a balance to the stimulatory effects of BDNF on neuronal differentiation in the hippocampus. Golgi staining in OFQ knockout (KO) mice revealed an increase in primary dendrite length as well as spine density, suggesting that endogenous OFQ inhibits dendritic morphology. We have also used cultured hippocampal neurons to demonstrate that exogenous OFQ has an inhibitory effect on dendritic growth and that the neuropeptide alters the response to BDNF when pre-administered. To determine if BDNF and OFQ act in a feedback loop, we inhibited the actions of the BDNF and OFQ receptors, TrkB and NOP using ANA-12 and NOP KO mice respectively but our data suggest that the two factors do not act in a negative feedback loop. We found that the inhibition of dendritic morphology induced by OFQ is via enhanced RhoA activity. Finally, we have evidence that RhoA activation is required for the inhibitory effects of OFQ on dendritic morphology. Our results reveal basic mechanisms by which neurons not only regulate the formation of proper dendritic growth during development but also control plasticity in the mature nervous system.
authors.affiliation: Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey.
authors.forename: Janet
authors.initials: J
authors.lastname: Alder
authors.forename: Seth
authors.initials: S
authors.lastname: Kallman
authors.forename: Alicia
authors.initials: A
authors.lastname: Palmieri
authors.forename: Farah
authors.initials: F
authors.lastname: Khadim
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Ayer
authors.forename: Sujata
authors.initials: S
authors.lastname: Kumar
authors.forename: Katherine
authors.initials: K
authors.lastname: Tsung
authors.forename: Ilya
authors.initials: I
authors.lastname: Grinberg
authors.forename: Smita
authors.initials: S
authors.lastname: Thakker-Varia
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology*; D018847:Opioid Peptides / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009479:Neuropeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C526380:RhoA protein, mouse; C000722287:Oprl1 protein, mouse
keywords: RhoA; brain-derived neurotrophic factor; dendrite; neuropeptide; orphanin FQ/nociceptin